WO2002096393A1

WO2002096393A1 - Anorexic composition comprising calcium acetate

Info

Publication number: WO2002096393A1
Application number: PCT/ZA2002/000092
Authority: WO
Inventors: Hester Hendrina Vorster; W. Alan Tomlinson
Original assignee: Potchefstroom University For Christian Higher Education
Priority date: 2001-05-29
Filing date: 2002-05-29
Publication date: 2002-12-05
Also published as: CN1520284A

Abstract

This invention provides an anorexic composition comprising calcium acetate in a form suitable for oral consumption and absorption in the stomach and small intestines. The anorexic composition includes a flavouring agent for hiding the taste of the calcium acetate, thus rendering the composition suitable for oral consumption and absorption in the stomach and small intestines. The anorexic composition further includes a sweetener and fruit pectin. This invention further relates to a method of treating obesity, including the steps of administering to a person in need thereof the said anorexic composition. Preferably the anorexic composition is administered in the form of a beverage or foodstuff. The method includes the step of administering a sufficient amount of the anorexic composition to the said person in need thereof at least twice daily so that an effective amount of between 3 g and 7 g, preferably 5 g, calcium acetate is administered to the said person.

Description

ANOREXIC COMPOSITION COMPRISING CALCIUM ACETATE

This invention relates to an anorexic composition and the use thereof in the treatment of obesity.

The Applicant's South African patent number 97/7300 relates to a pharmaceutical agent for the prevention or treatment of any of the following conditions in mammals: atherosclerosis, thrombosis, unwanted high levels of free radicals, unwanted long fibrin clot lysis times, unwanted fibrin clot characteristics, unwanted high levels of free fatty acids and obesity and the use thereof. The agent comprises calcium acetate in a pharmaceutically acceptable protective coating which is resistant to digestion and solution in the stomach and small intestine of a mammal, but digestible or soluble in the colon of a mammal. The calcium acetate is released in the colon of a patient and not in the stomach and small intestines.

A disadvantage of calcium acetate in powder form is that it is foul tasting and not suitable for oral consumption.

Another disadvantage of calcium acetate is that, in order to consume therapeutical ly effective amounts thereof in tablet form up to 15 tablets have to be administered orally three times daily. This is not practical nor commercially viable. The Applicant has investigated methods for preparing an anorexic composition based on the above agent and it is accordingly an object of the present invention to provide an anorexic composition and the use thereof in the treatment of obesity which are improvements to the invention disclosed in the above patent.

According to a first aspect of the invention there is provided an anorexic composition comprising calcium acetate in a form suitable for oral consumption and absorption in the stomach and small intestines.

Further according to the invention the anorexic composition includes a flavouring agent for hiding the foul taste of the calcium acetate, thus rendering the composition suitable for oral consumption and absorption in the stomach and small intestines.

The calcium acetate may constitute between 54% and 89.9 % on a mass per mass basis of the anorexic composition.

The flavouring agent may constitute between 5 and 20 % on a mass per mass basis of the anorexic composition.

The anorexic composition may include a sweetener. The sweetener may constitute between 5 to 25 % of the anorexic composition on a mass per mass basis.

The anorexic composition may include fruit pectin.

The fruit pectin may constitute between 0.1% and 1% on a mass per mass basis of the anorexic composition.

The anorexic composition may be in the form of a powder which is soluble in water.

According to a second aspect of the invention there is provided a method of treating obesity, including the steps of administering to a person in need thereof an anorexic composition according to the first aspect of the invention.

The anorexic composition may be administered in the form of a beverage or foodstuff.

The method may include the step of administering a sufficient amount of the anorexic composition to the said person in need thereof at least twice daily so that an effective amount of between 3g and 7g calcium acetate is administered to the person. Preferably an effective amount of 5g calcium acetate is administered to the said person twice daily.

A preferred embodiment of the invention will now be described by way of the following non-limiting example:

EXAMPLE 1

1. METHODS

1.1 Study design

The main objective of the study was to examine the effect of an anorexic composition in accordance with the invention on weight loss in obese subjects who were prescribed an energy restricted diet. A double-blind, placebo-controlled design was chosen in which two parallel groups of subjects followed the diet, supplemented with either the anorexic composition mixed with a micronutrient blend or the micronutrient blend on its own without the anorexic composition. A third group followed the diet supplemented with a placebo product for 12 weeks. From a comparison of baseline and end values within groups and changes from baseline to end between groups in this design enabled the Applicant to assess the effects of the anorexic composition and the micronutrient blend compared to those observed in the placebo group. 1.2 Participating subjects

120 Obese volunteers were recruited and screened in the metabolic unit of the Applicant. The following criteria were used:

Inclusion criteria: male or female; age between 21 and 45 years; body mass index (BMI) > 27 kg/m²; willingness to comply to interventions;

Exclusion criteria: pregnancy; lactation; any chronic disease; use of chronic medication and or nutritional supplements.

The study protocol and procedures were explained to these volunteers, and 80 subjects who met the criteria signed an informed consent form. These 80 subjects (9 men and 71 women) were randomly allocated to three groups and asked not to make major lifestyle changes during the 12 week study period, except those related to the diet and supplement intervention. The mean ages, body weight, height and BMI of the three groups at baseline are given in Tables 4.2 and 4.3. Because the number of male subjects was small, no differences in responses of men and women were calculated.

1.3 The interventions

1.3.1 Diet

An energy restricted (slimming) low-fat diet was prescribed to each participant. The type of foods and portion sizes in this diet were chosen to provide between 5000 and 6000 kilojoules daily. The diet and the principles of weight loss were explained to each subject. Foods on the diet sheet not usually eaten by subjects were replaced by low-fat alternatives. A nutrient analysis of a daily intake selected from the diet prescribed to women was prepared. This analysis showed that it was possible to reduce energy intake even below 5000 kilojoules on this diet, depending on portion sizes. However, at this low energy intake, the micronutrient intakes would be compromised if a micronutrient supplement is not used (which was not allowed in this study). The participating subjects were asked to follow the diet as far as possible. They were informed that if they did not loose weight, it would be a sign that they did not comply to dietary instructions. It was accepted that following the low-fat principles and smaller portions of the diet, an energy deficit of at least 2000 kilojoules per day was reachable, translating to a weight loss of 4.4 kg over a 12 week (84 day) period.

1.3.2 Supplements

In conjunction with the diet, each of the three groups took a supplement twice ^• daily before two meals (by choice this was mostly before breakfast and supper). The supplements consisted of a powder of which 5 ml (1 teaspoon) had to be dissolved in a glass of water by stirring for a few seconds and then drank immediately before the meal. The composition of the supplements is given Table 1. Group 1 received a mixture of a micronutrient blend and an anorexic composition in accordance with the invention. Group 2 received the placebo supplement consisting of lactose, colour and flavour agents. Group 3 received the same formula as Group 1 , except that the anorexic composition was not included. A dosage of 5 ml twice daily resulted in an intake of 5 grams of the anorexic composition by Group 1 , providing an additional calcium intake of 1265mg per day. Between 0.1% and 1% fruit pectin were added to the group 1 and group 3 compositions.

Table 1 Composition of the supplements per 10 ml_ daily dose

1.4 Measurements

For the screening process, subjects filled in a demographic and medical history questionnaire. They were weighed, heights measured and body mass index calculated. The baseline measurements were made on the day the subjects of the three randomised groups were prescribed the energy- restricted diet and received their supplements. These measurements included anthropometry, 24-hour dietary intake recall and blood sampling for measurements of biochemical variables. The baseline measurements were repeated after 12 weeks to obtain the end values. In addition, the subjects visited the Metabolic Unit of the Applicant on a once-weekly basis to be weighed, compliance to the interventions monitored, and to receive their supplements. The methods used for measurement of all these variables and normal ranges/cut points where applicable are summarised in Table 2.

Table 2 : Methods used to measure variables: baseline and end

1.5 Statistical analysis

The data were computerised, cleaned (double checked), and analysed, using the SPSS programme (Version 9). A paired samples test was used to compare baseline and end values within each group. Because the groups were small, a non-parametric test, the Kruskal-Wallis test, was used to compare the changes from baseline to end between groups.

1.6 Ethical considerations

The Ethics Committee of the Applicant approved the study (Ethics Committee number OOM22). All subjects signed a written consent form. Persons, who volunteered, but did not meet the inclusion criteria, were given the option to join the Lipid Clinic of the Applicant in the Metabolic Unit for screening of serum lipids and dietary advice.

2. RESULTS

2.1 Subjects

Table 3 shows that of the 80 subjects recruited, 5 (all women) dropped out (3 in Group 1 , and one each in the other two groups). Two subjects in Group 1 found the diet unacceptable; while three had other unrelated medical problems that prevented them from further participation. During, and at the end of the study, notes were made regarding compliance (acceptability) to the diet and the product. While still being "blinded" to the interventions, subjects who indicated that they did not comply with the product were selected as "non-compliers". Table 3 indicates that there were 10 non- compliers in Group 1 , two in Group 2 and four in Group 3.

TABLE 3 NUMBERS OF PARTICIPATING SUBJECTS

Group 1 : Anorexic composition

Group 2: Placebo

Group 3: micronutrient blend, (micronutrient blend without acetate)

Table 4 shows that there were no significant differences in the mean ages of the three groups, nor between that of the compliers and non-compliers in each group.

TABLE 4 AGE AND HEIGHT OF COMPLIERS AND NON-COMPLIERS IN EACH GROUP

C= compliers (see text) NC= Non-compliers (see text)

Group 1 : Anorexic composition plus diet

Group 2: Placebo plus diet

Group 3: micronutrient blend plus diet 2.2 Changes in weight and body mass index

Table 5 shows that there were significant reductions in the mean body weights and body mass index (BMI) of the compliers in all three groups. Table 5 also shows that the 9.2 kg lost by Group 1 , was significantly more than the 5.8 kg lost by Group 2. The reduction in BMI of 3.3 kg/m² of Group 1 was significantly larger than that of the Group 2 (2.1 kg/m²) as well as that of Group 3 (1.9 kg/m²). As expected, the weight loss in the non-compliers of each group was less than that of the compliers.

TABLE 5 : WEIGHT AND BODY MASS INDEX OF COMPLIERS AND

NON-COMPLIERS

C= Compliers (see text) NC= Non-compliers (see text)

BMI = body mass index

SD = standard deviation a,b,c...means with the same symbol differ significantly (p<0.05): within groups, paired samples test; The changes between groups, Kruskal-Wallis test (non-parametric) Group 1 : Anorexic composition plus diet

Group 2: Placebo plus diet

Group 3: micronutrient blend plus diet 2.3 Changes in body circumferences

Table 6 illustrates that the changes in body weight of all three groups of compliers were accompanied by significant reductions in waist, hip, thigh and mid-upper arm circumferences. Except for hip and mid-upper-arm circumferences in Group 2, these reductions were larger in Group 1 , although not significantly so.

TABLE 6 : BODY CIRCUMFERENCES OF COMPLIERS AND NON- COMPLIERS

C= compliers (see text) NC= Non-compliers (see text) BMI = body mass index

SD = standard deviation a,b,c... means with the same symbol differ significantly (p<0.05): within groups, paired samples test; between groups, Kruskal-Wallis test (non-parametric)

Group 1 : Anorexic composition plus diet

Group 2: Placebo plus diet

Group 3: micronutrient blend plus diet

2.4 Changes in haematological variables

The changes in haemoglobin, haematocrit and plasma fibrinogen are shown in Table 7. The compliers of all three groups had a significant reduction in haemoglobin, although the mean end values were still in the normal range of 8.7-11.2 mmol/L for men and 7.5-9.9 mmol/L for women.

The reductions in haematocrit were significant in Groups 1 and 2. During baseline, Group 2 had a significantly lower value than Group 1. However, the changes in the compliers of the three groups of 1.1 and 4.0 mmol/L were not statistically significant.

Table 7 also shows the changes in plasma fibrinogen. The compliers in Groups 1 and 2 had small but statistically significant increases in plasma fibrinogen (0.13 and 0.12 g/L). The non-compliers in these two groups had very small, non-significant decreases. Subjects in Group 3 who complied to the product had a small but significant decrease (0.05 g/L) in plasma fibrinogen.

TABLE 7 : HAEMATOLOGICAL VARIABLES OF COMPLIERS AND NON- COMPLIERS IN EACH GROUP.

No value (s) available C= compliers (see text)

NC= Non-compliers (see text)

BMI = body mass index

SD = standard deviation a,b,c... eans with the same symbol differs significantly (p<0.05): within groups, paired samples test; between groups, Kruskal-Wallis test (non-parametric)

Group 1 : Anorexic composition plus diet

Group 2: Placebo plus diet

Group 3: micronutrient blend plus diet

10

2.5 Changes in serum lipids and lipoproteins

Table 8 gives the changes in serum total, LDL-, and HDL-cholesterol, as well as serum triglycerides. Although none of these changes were statistically significant within groups or between the groups of compliers, it should be noted 15 that there were small reductions in total and LDL-cholesterol. HDL-cholesterol did not change. However, serum triglycerides of the Group 1 showed an increase from 1.19 to 1.68 mmol/L. This increase was not statistically significant but may represent clinically significant increases in some compliers.

20 TABLE 8: MEAN (STANDARD DEVIATION) NUTRIENT INTAKES* OF COMPLIERS AND NON-COMPLIERS OF EACH GROUP

2.6 Dietary intakes

The mean nutrient intakes of the compliers and non-compliers of the three groups were given in Table 8. These intakes were measured by the 24-hour recall method using baseline and end of the project. Table 8 shows that Group 1 reported a 2174kJ lower intake at the end compared to baseline, Group 2 a 2505kJ lower intake and Group 3 a 1515 kJ intake. Table 8 also shows that these reductions in energy intake were mainly because of lower fat and added sugar intakes.

10 TABLE 9 SERUM LIPIDS IN MMOL/L OF COMPLIERS AND NON- COMPLIERS IN EACH GROUP

LDL-C = Low-density lipoprotein cholesterol HDL-C = high-density lipoprotein cholesterol C= compliers (see text)

NC= Non-compliers (see text) BMI = body mass index SD = standard deviation a,b,c... means with the same symbol differs significantly (p<0.05): within groups, paired samples test; between groups, Kruskal-Wallis test (non-parametric) Group 1 : Anorexic composition plus diet Group 2: Placebo plus diet Group 3: micronutrient blend plus diet

3. DISCUSSION

3.1 Compliers and non-compliers

The main objective of this study was to assess the effect of two interventions, both potential weight reduction agents, formulas, supplements or products on weight loss in obese subjects following and energy restricted diet, compared to a placebo group who followed the diet plus an inactive placebo. In a study of this nature it is always difficult to measure dietary compliance. But because the effects of the two particular products were examined, it was decided to measure compliance to the prescribed products (as well as to the placebo product) during personal weekly interviews when the subjects were weighed, as well as at the end of the 12 week study. This distinction between "compliers" and non-compliers" should not be confused with "responders and "non-responders". In the latter case, subjects who complied with an intervention, but who did not show expected outcomes, are often depicted as "non-responders". Because reported compliance to the product, and not the outcome, namely weight loss, was used as criteria to distinguish between compliers and non- compliers, comparison of these two-subgroups within each group and comparison of the three groups of compliers are valid to assess the effects of the different products. However, the groups of non-compliers to the products also lost some weight (1.6, 2.3 and 2.8 kg respectively), indicating that these subjects followed the energy restricted diet to some extent. The weight loss in the Group 2 also indicates that dietary compliance was acceptable in some. This suggests that non-compliers to the products probably had problems complying to the diet. It seems that there could have been differences in the level of motivation to loose weight in these subjects.

Adherence to an energy restricted diet by obese subjects is a problem, and underreporting of energy intake by obese persons is an accepted phenomenon (7). Using reported dietary intakes as a measure of compliance is therefore problematical. Nevertheless, the reported dietary intakes of these subjects at baseline and at the end of the study, are given in annexure 4. The reported dietary intakes were those of the previous day, and not habitual intakes (as can be measured by a food frequency questionnaire). Because of the known underreporting of obese subjects, it was argued that the risk of underreporting may be lower during a 24 hour recall.

Group 2 reported the largest mean energy deficit and Group 3 the smallest. It is of significance that Group 1 , despite loosing the most weight, did not report a larger energy deficit. This suggests that the anorexic composition may also have effects on energy expenditure (not only intake). However, this study was not designed to examine mechanisms.

3.2 Weight loss

The results shown in Table 5 indicate that subjects of Group 1 lost significantly more weight than Group 2, and reduced their BMI significantly more than the compliers in both Groups 2 and 3.

The compliers Groups 2 and 3 both lost a mean of 5.8 and 5.5 kg over the 12 week (84 days) period, indicating that these subjects achieved an energy deficit of approximately 220 400 and 209 000 kilojoules over this period. This translates to a daily mean energy deficit of between 2 488 and 2 624 kilojoules. The additional 3.4 kg that Group 1 subjects lost, mean an additional 129 200 kilojoules energy deficit over 12 weeks or 1 538 kilojoules per day. In total, a mean deficit of 4 162 kilojoules per day was accomplished by the subjects of Group 1.

As already mentioned in 5.1 the question that needs to be answered is whether this "additional" effect on weight loss caused by the anorexic composition is a result of decreased intakes (better compliance to the energy-restricted diet) because of appetite suppression, or whether the anorexic composition has an independent effect on metabolism? At high doses it has been reported that calcium, one of the substances in the anorexic composition, may act as an anorexic agent (8). Whether the amount of additional calcium (1265mg/day) provided by the anorexic composition would suppress appetite remains to be determined. Nevertheless, it seems prudent to advise that subjects who take the micronutrient blend should follow a low calcium diet.

3.3 Body circumferences

Body circumferences (Table 6) were significantly reduced in the compliers of all three groups. If the mean values of waist and hip circumferences are used to calculate waist: hip ratios, it seems that reductions in waist circumferences were slightly larger than hip circumferences. The result is a slight reduction of waist: hip ratios of 0.032, 0.007 and 0.015 in Groups 1 , 2 and 3 respectively. The waist: hip ratio may be used to distinguished between android or upper-

body obesity and gynoid or lower-body obesity (1). A value of > 1.0 for men

and 0.85 > for women is regarded as indicative of android obesity (1). All three

groups had baseline values of >0.800. The larger reduction in Group 1 (from

0.838 to 0.806) is probably because of the larger weight loss.

4 CONCLUSIONS

4.3 Major finding

The major finding of this study was therefore that those subjects that complied in taking the anorexic composition twice daily for 12 weeks lost significantly more weight and could reduce their BMI significantly more than subjects who took the placebo or the micronutrient blend regularly. Furthermore, by presenting the calcium acetate in a form suitable for oral consumption, as a liquid drink, the anorexic composition is further made practical and commercially viable.

4.4 Conclusion

The conclusion that can be drawn from these results it that the anorexic composition is an effective weight reducing agent that will help those subjects following an energy-restricted diet to loose more weight. Because this effect was not observed for the micronutrient blend supplement on its own without the anorexic composition, it seems that the anorexic composition was indeed responsible for the additional weight loss.

4.5 Recommendation

The anorexic composition can therefore be recommended as an effective weight loss supplement which will help obese subjects following an energy- restricted diet to loose more weight than on the diet alone. By presenting the calcium acetate in a drinkable and palatable format, by hiding the vial taste thereof, a commercially viable and practically acceptable product is provided by the present invention.

The Applicant therefore foresees that an anorexic composition and method of treating obesity according to the invention present an efficient means of reducing weight.

It will be appreciated that variations in detail are possible with an anorexic composition and the use thereof according to the invention without departing from the scope of the appended claims.

References

1. World Health Organization. Obesity. Preventing and managing the global epidemic. Report of a WHO consultation on obesity. Geneva, WHO, 1998: 1-276.

2. Walker ARP. Obesity outlook: hopeful or hopeless? Editorial. SAJ Epidemiol Infect 2000; 15(4): 87-88.

3. Rosenbaum M, Leibel RL, Hirsch J. Obesity. N Eng J Med 1997; 337: 396-407.

4. Walker ARP. Obesity: the new pill - any practicable improvements? S Afr J CIin Nutr 2000; 13(1 ) : 4-6.

5. Veldman FJ, Nair CH, Vorster HH, Vermaak WJ, Jerling JC, Oosthuizen W, Venter CS. Possible mechanisms through which dietary pectin influences fibrin network architecture in hypercholesterolaemic subjects. Thrombosis Research 1999; 93(6): 253-264.

6. Potchefstroom University for Christian Higher Education: Patent.

7. Kruger HS. The puzzle of obesity ion African women: contributing factors and associated risk factors. Ph.D. thesis. PU vir CHO. 1999: 1-210.

8. Reynolds JEF ed. Martindale. The extra pharmacopoeia. London, Pharmaceutical Press 1993; 853-855. 9. Anderson JW. Short-chain fatty acids and lipid metabolism: human studies. In: Cummings JH, Rombeau JL, Sakata T. Eds. Physiological and clinical aspects of short-chain fatty acids. Cambridge University Press, 1995: 509-523.

10. Venter CS, Vorster HH. Possible metabolic consequences of fermentation in the colon of humans. Medical hypothesis, 1989; 29(3): 161- 166.

11. Meyer BJ, Meij HS, Labuschagne CJJ et al. Eds. Die fisiologiese basis van geneeskunde. Pretoria, HAUM 1988; 24.1-24.3.

12. Vorster HH, Badenhorst C, Barnard HC, Walker ARP, Kruger MM, van Jaarsveld P. Effects of weight reduction on plasma fibrinogen levels and other metabolic variables in obese women. S Afr J Clin Nutr 1989; 2(2): 8- 15.

13. Vorster HH, Cummings JH, Jerling JC. Diet and haemostatic processes. Nutrition research reviews 1997; 10: 115-135.

14. Vorster HH, Venter CS. Why fibrinogen should be measured as part of the coronary heart disease risk profile. S Afr Med J 1993; 83: 309-310.

15. Mann J. Cardiovascular diseases. In: Mann J, Truswell AS. Eds. Essentials of human nutrition. Oxford, Oxford University Press 1998: 279- 307. 16.Wolmarans P, Oosthuizen W. Eat fat sparingly - implication for health and disease. S Afr J Clin Nutr 2001 ; 14(3): S 48-S55.

17. Venter CS, Vorster HH, Cummings JH. Effects of dietary propionate on carbohydrate and lipid metabolism, in healthy volunteers. Am J Gastroenterol 1990; 85: 549-553.

Claims

1. An anorexic composition comprising calcium acetate in a form suitable for oral consumption and absorption in the stomach and small intestines.

2. An anorexic composition according to claim 1 which includes a flavouring agent for hiding the foul taste of the calcium acetate, thus rendering the composition suitable for oral consumption and absorption in the stomach and small intestines.

3. An anorexic composition according to claim 1 or claim 2 wherein the calcium acetate constitutes between 54% and 89.9 % on a mass per mass basis of the anorexic composition.

4. An anorexic composition according to claim 2 wherein the flavouring agent constitutes between 5 and 20 % on a mass per mass basis of the anorexic composition.

5. An anorexic composition according to any one of the preceding claims which includes a sweetener.

6. An anorexic composition according to claim 5 wherein the sweetener constitutes between 5 to 25 % of the anorexic composition on a mass per mass basis.

7. An anorexic composition according to any one of the preceding claims which includes fruit pectin.

8. An anorexic composition according to claim 7 wherein the fruit pectin constitutes between 0.1% and 1% on a mass per mass basis of the anorexic composition.

9. An anorexic composition according to any one of the preceding claims which is in the form of a powder which is soluble in water.

10. A method of treating obesity, including the steps of administering to a person in need thereof an anorexic composition according to any one of claims 1 to 9 and 14.

11. A method according to claim 10 wherein the anorexic composition is administered in the form of a beverage or foodstuff.

12. A method according to claim 10 or 11 which includes the step of administering a sufficient amount of the anorexic composition to the said person in need thereof at least twice daily so that an effective amount of between 3g and 7g calcium acetate is administered to the said person.

13. A method according to claim 12 wherein an effective amount of 5g calcium acetate is administered to the said person twice daily.

14. An anorexic composition substantially as herein described and exemplified.

15. A method of treating obesity substantially as herein described and exemplified.